Di-bis(p-chlorophenoxy) acetic acid esters of dimethylol pyridines



United States Patent 3,542,795 DI-BIS(p-CHLOROPHENOXY) ACETIC ACIDESTERS 0F DIMETHYLOL PYRIDINES Rudolf G. Griot, Florham Park, N.J.,assignor to Sandoz, Inc., Hanover, NJ.

No Drawing. Continuation-impart of application Ser. No. 748,234, July29, 1968. This application Oct. 22, 1968,

Ser. No. 769,725

' Int. Cl. C07d 31/34 US. Cl. 260-295 2 Claims ABSTRACT OF THEDISCLOSURE The compounds are esters of derivatives of acetic acid andcontain a plurality of bis-(p-halophenoxy) acetoxy functions, e.g., thebis-p-chlorophenoxyacetic acid ester of ethylene glycol, and are usefulas hypocholesteremic agents.

n is a whole integer of from 2 to 6; X is a halogen atom having anatomic weight of from 35 to 80, i.e. a chlorine or bromine atom; and Ais either a saturated lower aliphatic hydrocarbon moiety having 2 to 6units of valency, e.g., having from 2 to 6 carbon atoms, such as -CH CHor C-'(-CH the number of units of valency of A being equal to n and nocarbon atom having more than one unit of valency; or

a divalent function of the structure:

wherein X is a halogen having an atomic weight of from 35 to 80, i.e. achlorine or bromine atom, then n=2; or a dimethylol pyridine residuehaving the formula Compounds I are obtainable by esterifying (Step A) aCompound 3,542,795 Patented Nov. 24, 1970 wherein X is as defined above;and Y is a halogen atom having an atomic weight of from 35 to 80, i.e. achlorine or bromine atom, with a Compound III wherein A and n are asdefined above. Advantageously at least n moles of Compound II per moleof Compound III should be provided to the reaction. Preferably a 5% to50% molar exces of Compound II is used in the reaction, over thatrequired to satisfy the molar ratio n II=III.

The esterification (Step A) may be carried out in a suitable inertorganic solvent, e.g., benzene, toluene, chloroform and diethyl ether,and at a temperature of 20 C. or below. Step A, if desired, may becarried out at elevated temperatures; however, in such instances,external cooling should be provided since the reaction is exothermic.Preferably the reaction is carried out at a temperature of from about-10 to about 5 C. It is advantageous to provide a means for removing thehydrogen halide liberated by the reaction, e.g., by carrying out thereaction in the presence of an acid binding agent, such as an alkalimetal carbonate, e.g., potassium carbonate, or suitable organic base,e.g., pyridine or triethylamine.

Alternatively, a Compound I may be obtained by transesterifying (Step B)a Compound III with a Compound 'IV o o X) 2 2 IV wherein X is as definedabove, Z is (lower)alkoxycarbonyl having the formula 0 R-O-(L- wherein Ris lower alkyl, preferably unbranched alkyl having from 1 to 4 carbonatoms; and Z is either Z or a hydrogen atom.

A Compound IV wherein Z is a hydrogen atom is a Compound IVa i.e. anacetic acid ester derivative. A compound IV wherein Z is(lower)a1koxycarbonyl is a Compound IVb, i.e. a malonic acid diesterderivative.

Step B is carried out employing a Compound IVa, in a conventional mannerfor transesterifying an ester and an alcohol, e.g., in an inert organicsolvent and in the presence of an alkali metal alkoxide, preferablysodium methoxide or ethoxide. Preferably, a temperature of at least 50C. is utilized, e.g., at reflux temperature of the solvent. However,when employing a compound IVb, Step B is carried out in the same manneras for a Compound IVa, except that the temperature should besuificiently high for partial decarboxylation to occur, a temperature ofat least 70 C. being desirable for this purpose, and the solvent shouldhave a boiling point of not less than C., e.g., benzene, toluene orxylene.

Compounds II, dimethylol pyridines, as well as Compounds IIIa, i.e.Compounds III 'wherein A is a saturated lower aliphatic hydrocarbonmoiety, are known and may be prepared by methods known per se; or wherenot known, they may be prepared by methods analogous to the methods forpreparing known compounds. Compounds suitable as Compounds II includebis-(pchlorophenoxy) acetyl chloride. Compounds IIIa may be unbranched,e.g., ethylene glycol, glycerol or mannitol, or branched, e.g.,pentaerythritol, or alicyclic, e.g., insoitol. Preferred Compounds 111::include diols, triols and tetrols. Preferred Compounds IIIa are thosehaving from 1 to 1.5 carbon atoms per unit of valency.

Compounds IV are readily prepared by condensing a Compound V, i.e. anappropriate alkali phenolate, with a Compound VI, i.e. a di(lower)alkyldihalomalonate or (lower)alkyl dihaloacetate), by known means (Step C).

wherein Z and Z are as defined above and X is halo having an atomicweight of 35 to 80, i.e. bromo or chloro.

Step C (the condensation) is readily carried out in a suitable inertorganic solvent, e.g., dimethylacetamide, diethylacetamide anddimethylformamide, and at from 20 to 80 C., preferably from 20 to 30 C.,using a molar ratio of Compound V to Compound VI of at least 2:1.Preferably Compound V is a sodium or potassium pheno late. The Z and Zsubstituents of the resultant Compound IV correspond to the Z and Zsubstituents of the Compound VT starting material.

A Compound III, which is an appropriate 2,2-bis(phalophenoxy)-l,3propanediol, is obtainable by reduction of an appropriate Compound IVb,e.g., bis(p-chlorophenoxy)malonic acid dialkyl ester is reduced to form2, 2 bis-(p-chlorophenoxy)-l,3-propanediol. The reduction isconveniently effected in an inert organic solvent, preferably a loweralkanol, such as methanol or ethanol, employing an appropriate hydridereducing agent. The reduction is preferably effected employing sodiumborohydride although ltihium aluminum hydride can also be used. Theredutcion of the bis-(p-halophenoxy)malonic acid dialkyl ester (IV withsodium borohydride results in the formation of the intermediate boroncomplex of the formula X/Q-O o-cm O-X X XQ-O 0112-0 p-on:

Such complex can be readily isolated in conventional wherein X is asdefined above.

manner or converted in situ to the desired diol (a Compound III) bytreatment with aqueous ammonia solution or aqueous sodium fluoridesolution. The reduction is preferably carried out at refluxedtemperature although elevated temperatures up to reflux temperature canbe employed. The resulting diol can be readily isolated employingconventional techniques.

Various of the alcohols, alcoholates, phenols and phenolates employed asreactants above are known and are prepared according to methodsdisclosed in the literature. Those others not specifically desired inthe literature are prepared by analogous methods from known materials.

The compounds of Formula I are useful because they possesspharmacological properties in animals. In particular these compounds areuseful as hypocholesteremics/ hypolipemics, as indicated by theiractivity in a group of white rats which are given 30 milligrams perkilogram of body weight per diem of the compound orally, for 6 days, andthen anesthetized with sodium hexabarital, bled and then tested byextracting serum or plasma with isopropanol and noting the cholesteroland triglyceride contents of the extracts as compared to those of acontrol group. The cholesterol and triglyceride contents are determinedby the methods described by Lofland, H. B., Anal Biochem, 9:393 (1964)(Technicon method N 24a); and Kessler, G., and Lederer, H. TechniconSymposium, Mediad Inc., New York, pp. 345-347, (1965 respectively. Forsuch usage, the compounds may be administered orally as such or admixedwith conventional pharmaceutical carriers or administered orally in suchforms as tablets, dispersible, powders, granules, capsules, syrups andelixirs. Such compositions may be prepared according to any methodsknown in the art for the manufacture of pharmaceutical compositions, andsuch compositions may contain one or more conventional adjuvants, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide an elegant and palatable preparation.Tablets may contain the active ingredient in admixture with conventionalpharmaceutical excipients, e.g., inert diluents such as calciumcarbonate, sodium carbonate, lactose and talc, granulating anddisintegrating agents, e.g., starch and alginic acid, binding agents,e.g., starch, gelatin and acacia, and lubricating agents, e.g.,magnesium stearate, stearic acid and tale. The tablets may be uncoatedor coated by known techniques to delay disintegration and adsorption inthe gastro-intestinal tract and thereby provide a sustained action overa longer period. Similarly, suspensions, syrups and elixirs may containthe active ingredient in admixture with any of the conventionalexcipients utilized for the preparation of such compositions, e.g.,suspending agents (methylcellulose, tragacanth and sodium alginate),wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylenesorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin.

For the treatment of hypercholesteremia/hyperlipemia, noted above, thedosage administered may vary depending on the particular compoundemployed and the severity of the condition being treated. In general,satisfactory results are obtained when administered at a daily dosage offrom about 4 milligrams to about 30 milligrams per kilogram of animalbody weight, preferably given in divided doses, 2 to 4 times a day, orin sustained release form. For most mammals the total daily dosage isfrom about 0.25 gram to about 2 grams of the compound, and the dosageforms suitable for internal use comprise from about 50 milligrams toabout 1000 milligrams of active compound in intimate admixture with asolid or liquid pharmaceutically acceptable carrier or diluent. Thepreferred pharmaceutical compositions from the standpoint of preparationand ease of administration are solid compositions, particularlyhard-filled capsules and tablets containing from milligrams to about 500milligrams of the active ingredient.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques and containing thefollowing:

Ingredient: Parts by wt. 1,2-ethylene di-bis(p-chlorophenoxy)acetate 75Tragacanth 2 Lactose 14.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5

EXAMPLE 1 Bis(p-chlorophenoxy)acetic acid diester with thebis(pchlorophenoxy)acetal of dihydroxy acetone Step A.Preparation ofbis-(p-chlorophenoxy)malonic acid diethyl ester Sodium hydride inmineral oil (56.7%, 43.3 g. (1.0 mole), is washed with dry, low boilingpetroleum ether and the washed sodium hydride suspended in 1500 ml. ofdimethylacetamide. The resulting suspension is cooled to and 141.4 g.(1.10 moles) of p-chlorophenol is added with stirring to the cooledsuspension at such a rate that the temperature thereof does not exceed10 (external cooling with an ice/salt bath being employed as necessary).After all of the p-chlorophenol is added, the mixture is stirred for anadditional hour and then 159 g. (0.5 mole) of diethyldibromomalonate isadded to the mixture fairly rapidly allowing the temperature of themixture to rise to about 32. Stirring is continued for 88 hours and thenA of the solvent is evaporated in vacuo. To the resulting concentrate isadded 1500 ml. of ethyl acetate, and the mixture thus obtained is thenwashed twice with 1500 ml. (each) of water and twice with 750 ml. (each)of 2N aqueous sodium hydroxide. The washed organic phase is then driedover anhydrous magnesium sulfate, filtered and the filtrate evaporated.The residue is recrystallized from 95% ethanol to obtainbis-(p-chlorophenoxy)malonic acid diethyl ester, M.P. 48-50".

Step B.-Preparation of 2,2-bis (p-chlorophenoxy)- 1,3-propanediol To asolution of 206.5 g. (0.5 mole) of bis-(p-chlorophenoxy) malonic aciddiethyl ester in 2500 ml. of absolute ethanol is added, over a period of/2 hour, 66.2 g. (1.7-5 mole) of sodium borohydride while maintainingthe temperature of the reaction at about 35-45 The mixture is thenrefluxed for 4 hours, the ethanol evaporated oif and the residue (Boroncomplex) taken up in 2000 ml. of dimethylacetamide. To the resultant isadded (portionwise) 200 ml. of concentrated ammonium hydroxide, and theresulting mixture allowed to stand for /2 hour at room temperature (20)and then evaporated under a water aspirator vacuum at 7080. To theresidue is added 3000 ml. of ethyl acetate, and the resulting mixtureextracted twice with 2000 ml. (each) of water. The ethyl acetate layeris then dried over sodium sulfate. filtered and the ethyl acetateevaporated off. The resulting oil is added to 3000 ml. of carbontetrachloride, and the mixture cooled to room temperature to yield awhite voluminous fluffy crystalline product. After crystallization iscomplete, the mixture is cooled to 0 using an ice/salt bath. Thecrystalline product thus obtained is filtered off, washed first withcold 0) carbon tetrachloride and then with low boiling (30-60) petroleumether and then dried in a high vacuum oven at 50, to obtain2,2-bis-(p-chlorophenoxy)-l,3-propanediol, M.P. 87-8 9 The crude titlecompound is then crystallized from 300 ml. isopropanol, M.P. 112-1l6.

EXAMPLE 2 1,2-ethylene-di-bis (p-chlorophenoxy) acetate To 206 g. ofbis(p-chlorophenoxy)malonie acid ethyl ester in '62 g. of ethyleneglycol and 1.0 liter benzene, 4 g. of sodium methoxide are added and themixture distilled at atmospheric pressure.

After cooling the distillate, 500 ml. benzene and 25 0 ml. water areadded thereto and thoroughly mixed and the phases separated.

The benzene layer is evaporated in vacuo to obtain a residue which isthen dissolved in 250 ml. isopropanol. The resulting solution is treatedwith charcoal at reflux, filtered, and cooled to 0 causing a solid toseparate. The solid is collected and recrystallized twice from ethanolto yield the title compound, M.P. 93 "-96.

EXAMPLE 3 Bis(p-chlorophenoxy) acetic acid, ester with pentaerythritol2.72 g. (0.02 m.) of pentaerythritol, in 50 ml. of pyridine is cooled to0 and then treated with 200 ml. (0.1 m.) of a toluene solution ofbis-(p-chlorophenoxy)-acetyl chloride while maintaining the temperatureat 0-5 throughout the addition.

The mixture is allowed to stand for 66 hours at room temperature (25 C.)then the pyridine evaporated leaving a residue which is then dissolvedin 100 ml. of chloroform.

The chloroform solution is then washed with 50 ml. of 2 N hydrochloricacid, water, and two times with 50 ml. portions of saturated aqueoussodium bicarbonate solution.

The organic layer is separated, dried for 18 hours over magnesiumsulfate, and the solvent is evaporated to obtain the title product as ahighly viscous residue.

EXAMPLE 4 Bis-(p-chlorophenoxy)acetic diester of 2,6-dimethylol pyridineStep C.-Preparation of bis(p-chlorophenoxy)acetic acid diester with thebis(p-chlorophenoxy)acetal of dihydroxy acetone g. (0.244 mole) ofmethyl ester of bis-(p-chlorophenoxy) acetate and 17 g. (0.122 mole) of2,6 dimethylol pyridine are added to 250 ml. of toluene. 0.5 g. ofsodium methoxide is then added and the mixture brought to reflux duringa period of /2 hour, and then refluxed for 1 hour. The mixture is thencooled to room temperature, 100 ml. of toluene added and the mixturewashed with water. The toluene phase is dried over magnesium sulfate andthe solvent removed under vacuum to obtain a residue. The residue isthen crystallized from ethanol to obtain bis- (p-chlorophenoxy)aceticacid diester of 2,6-dimethylol pyridine, M.P. 100.

7 What is claimed is: 2. The compound of claim 1 wherein X is achlorine 1. A compound of the formula atom, and A is OH2 CH2- nReferences Cited q i h l b t UNITED STATES PATENTS e w er 10 27391523/1956 Krimmel 260295 X i il having an atomlc welght of from 3,332,9577/1967 Bencze 260-295 XR A is 3,413,298 11/1968 Biel et a1. 260295 15ALAN L. ROTMAN, Primary Examiner US. 01. X.R.

